Alzheimer's disease (AD) is the most common dementia among all of the clinically-recognized dementias in the aging population. About 5 million Americans currently suffer from AD, and 22 million other individuals in the world's population are projected to be afflicted by 2025. AD is a neurodegenerative disease of the central nervous system (CNS) that is characterized clinically by progressive loss of memory and other cognitive functions. AD is characterized macroscopically by brain atrophy reflecting neuronal and synaptic loss, and microscopically by the presence of neuritic plaques and neurofibrillary tangles. These insights suggest that treatments to delay the onset, slow the progression, and possibly prevent AD may be possible. A highly sensitive test capable of detecting AD in its earliest stages is needed in order to initiate treatment before significant neurological damage takes place.
To this end, discovery of highly sensitive biomarker(s) for the early diagnosis of AD is extremely important, since even under optimal conditions (i.e., with the presence of informants and thorough evaluation), the sensitivity and specificity of the clinical diagnosis of AD is approximately 80% accurate and currently known biomarkers are of similar reliability. In addition, new biomarkers may be useful in assessing disease progression or response to treatment.
In current clinical practice, the diagnosis of dementia due to AD is based almost entirely on clinical criteria. In addition to genetic analysis, biomarkers have the potential to increase diagnostic accuracy. Although not yet widely used in clinical practice, there are currently several biomarkers for AD that include a decrease in cerebrospinal fluid (CSF) Aβ42, an increase in CSF tau, an increase in isoprostanes, and a decrease in CSF sulfatide, as well as others. The sensitivity and specificity of these markers, at the earliest clinically recognizable stage of AD, has not been shown to be superior to clinically-based assessments at centers specializing in dementia evaluation.
Moreover, an increasingly important therapeutic issue is the identification of patients in the earliest clinically definable stages of AD or even at the pre-clinical stage of AD, so that pharmacotherapy can be maximally effective. Extensive AD pathology (plaques and tangles) develops over a 10 to 20 year period (i.e., pre-clinical AD) prior to any cognitive impairment or major cell loss. The presence of such a pre-clinical AD stage is evidenced by autopsies in which about 30% of subjects who die while cognitively normal in their mid-70's have marked AD pathology (i.e., plaques and tangles), but do not yet have the substantial cell loss that is present in those who die with mild cognitive impairment (e.g., see FIG. 1).
Lipidomics, defined as the large-scale study of the pathways and networks of cellular lipids, is an emerging and rapidly expanding research field, which has been catalyzed by the recognition that cellular lipids play many essential roles in cellular functions, and that the metabolism of individual lipid molecular species or lipid classes is interwoven. One of the major new developments in current lipidomics practice is the multi-dimensional mass spectrometry (MS)-based shotgun lipidomics. Through lipid class-selective intrasource ionization (e.g., see FIG. 2) and subsequent multi-dimensional MS analysis, shotgun lipidomics can fingerprint and quantitate individual molecular species of most of the major and many of the minor lipid classes in cellular lipidomes, which collectively represent >95% of the total lipid mass, and as many as 1,000 lipid molecular species, directly from the solvent extracts of a biological sample. The significance of this technology is that it allows virtually all molecular species of lipids present in biological samples to be screened in an unbiased fashion.